Summary Extracellular amyloid plaques are a defining feature of Alzheimer's disease brain pathology. A poorly understood aspect of these plaques is the massive abundance of lysosomes that selectively accumulate within dystrophic (swollen) axons that pass close to them. This axonal enrichment for lysosomes stands in sharp contrast to their near exclusion from the axons of healthy neurons. Beyond the potentially negative consequences of lysosome dysregulation on neuronal proteostasis and health, the enrichment within endosomes and lysosomes of proteases (? and ?-secretases) responsible for amyloid ? (A?) peptide production combined with the acidic environment of the lysosomal lumen that could further promote A? nucleation and suggests a vicious cycle whereby extracellular amyloid plaques trigger axonal membrane trafficking defects that result in abnormal lysosome accumulation and enhanced production/processing of A?. However, lysosomes also contain other proteases (cathepsins) that contribute to A? clearance. Due to these positive and negative contributions of lysosomes to A? metabolism, it is not clear whether the highly abundant lysosomes within dystrophic axons exert protective versus destructive effects on neuronal health. Thus, while there is evidence to suggest that modulating neuronal lysosome activity could represent a novel therapeutic opportunity, greater understanding of the functions of lysosomes in this context and of the basic cell biology that underlies this phenotype is required for the identification of the specific and relevant molecular targets. The proposed research builds on the unique experience in neuronal membrane traffic, lysosome homeostasis and in vivo imaging of the PI and co-PIs to address these problems in mouse models that recapitulate this Alzheimer's disease phenotype. To this end, we propose to: 1) investigate the mechanisms that give rise to the extreme abundance of lysosomes within Alzheimer's disease dystrophic axons; 2) take advantage of novel imaging-based assays for assessment of amyloid plaque formation and growth to dissect the relationship between amyloid plaque growth and neuronal lysosome function; and 3) evaluate specific strategies that modulate neuronal lysosome function in mice for their ability to protect neurons from the toxicity of abnormal ?- amyloid metabolism. These studies will test the hypothesis that abnormal neuronal lysosome functions are an important contributing factor to Alzheimer's disease pathology and may point to new therapeutic targets for the disease.?